The reduction of prochiral ketones produces an alcohol which contains an asymmetric carbon atom, designated by the asterik in the following reaction. ##STR1## Considerable effort has been expended in the past and continues to be expended in finding asymmetric reducing agents which will achieve the reduction of such carbonyl groups to give optically active alcohols of high optical purity (100% optical purity=100% ee).
One valuable reagent is B-isopinocampheyl-9-borabicyclo[3.3.1]nonane, B-Ipc-9-BBN, made by hydroborating optically active .alpha.-pinene with 9-borabicyclo[3.3.1]nonane (9-BBN) and sold by Aldrich Chemical Company under the registered trademark Alpine-Borane, and the modified borohydride reagent, NB-Enantride [M. M. Midland, A. Kazubski, J. Org. Chem., 47, 2495 (1982). ##STR2##
This reagent readily reacts with deuteroaldehydes, RCDO, to give the reduced product, a primary alcohol, in optical purities approaching 100% [M. M. Midland, S. Greer, A. Tramontano, S. A. Zderic, J. A. Chem. Soc., 47, 2352 (1979)]. ##STR3##
The .alpha.-pinene can be recovered and reused.
Originally, this reagent gave very poor results in the reduction of ketones. [A. Tramontano, Ph.D. Thesis, U. Cal. Riverside, (1980)], resulting in end product of only 7% optical purity. ##STR4##
However, it does reduce acetylenic ketones in high optical purity [M. M. Midland, A. Tramontano, A. Kazubski, R. S. Graham, D. S. Tsai, D. B. Cardin, Tetrahedron, 40, 1371 (1984)]. ##STR5##
Another modified borohydride reagent, K 9-O-DIPGF-9-BBNH is highly promising. [H. C. Brown, W. S. Park and B. T. Cho, J. Org. Chem., 51, 1934 (1986). ]
In addition, an enzymatic chiral reduction of ketones was recently reported by E. Keinan, E. K. Hafeli, K. K. Seth and R. Lamed, J. Am. Chem. Soc., 108, 162 (1986).
It still remains highly desirable to find a reagent that will do equally well in reducing aliphatic, alicyclic, and aromatic ketones. Indeed, it was discovered that carrying out the reaction under neat conditions or concentrated solutions provided product having 87% optical purity. [H. C. Brown and G. C. Pai, J. Org. Chem., 50, 1384 (1985).] ##STR6##
Even better results (94% optical purity) can be realized by carrying out the reduction under exceptionally high pressures, 6000 atmos. [M. M. Midland and J. I. McLoughlin, J. Org. Chem., 49 1317 (1984)]. ##STR7##
In 1 983, I reported the preparation of diisopinocampheylchloroborane via hydroboration of (+)-.alpha.-pinene (91.3% ee) with monochloroborane etherate (H.sub.2 BCl.OEt.sub.2) in ethyl ether at 0.degree. C. Herbert C. Brown et J. Am. Chem. Soc. 1983, 105, 2092-2093. The intermediate diisopinochloroborane was not isolated at that time, and it was subsequently discovered that the reaction described in that publication does not yield a pure, recrystallizable product. Rather than Ipc.sub.2 BCl, mixtures of optical isomers of Ipc.sub.2 BCl, IpcBCl.sub.2 and Ipc.sub.2 BH were obtained. It was impossible to crystallize chemically pure Ipc.sub.2 BCl from this mixture, and the mixture itself, which had an average optical purity of approximately 91.3% ee, was unsatisfactory for achieving asymmetric reduction of ketones in high enantiomeric excess. When the reduction of acetophenone using Ipc.sub.2 BCl prepared via the 1983 procedure, the product alcohol was only approximately 80% ee.
Unisolated, uncharacterized Ipc.sub.2 BCl was also reported by Uzarewicz, I. and Uzarewicz, A., Roczniki Chemii, 976, 50, 1351.
However, it was not until the advent of the present invention that it became possible to obtain chemically and optically pure diisopinocampheylhalohaloboranes, i.e., essentially 100% ee (enantiomeric excess). These valuable intermediates permit the preparation of alcohols of essentially 100% ee.
Thus, prior to the advent of the present invention, there remained a longstanding need for reagents which have an exceptional ability to achieve the reduction of many types of ketones in very high optical purities under very simple conditions. The present invention provides such reagents.